The Optimal LDL is not 50 to 70 mg/dL (P ...

The Optimal LDL is not 50 to 70 mg/dL (Part 2)

Oct 09, 2022

Continuing from Part 1, let us look at the topic of atherosclerosis.

O’Keefe and colleagues state:

Evidence from hunter-gatherer populations while they were still following their indigenous lifestyles showed no evidence for atherosclerosis, even in individuals living into the seventh and eighth decades of life.

This is false. Although autopsy studies on hunter-gatherers and other similar populations are limited, available data suggest that they did have atherosclerosis.

For the Inuit, Young notes (1):

Several autopsy series among Alaskan Eskimos and Canadian Inuit (Arthaud, 1970; Lederman et al., 1962) during the 1950s and 1960s indicate that cases of atherosclerosis, while not an important cause of death, were by no means absent.

Of course, the fact that they did have atherosclerosis is not evidence that blood cholesterol levels were responsible.

An autopsy study on the Inuit in 2003 reported "no obvious indication of a strong dependent association of lesions upon risk factors," including LDL + VLDL (2).

This is consistent with Wilber and Levine, who studied the Inuit living "close to their native diet" (3). These two researchers regarded the causative role of serum cholesterol in the development of atherosclerosis as "somewhat dubious" (4).

For the Bantu and Masai, Dr. George Mann stated (5):

Pepler and Meyer, Laurie et al. and Becker all agree that the Bantu are not free of atherosclerosis. We are finding with autopsy material that the Masai have atherosclerosis.

Indeed, Dr. George Mann later reported intimal thickening in the coronary arteries of the Masai and "extensive atherosclerosis" in the aorta despite a low average cholesterol level (125 mg/dL) (6).

As for the Bantu, Laurie and Woods made it a point to "correct the widely held opinion that they enjoy an immunity to this disease" (7). Autopsy studies of the Bantu revealed aortic atherosclerosis, coronary atherosclerosis, and cerebral vascular disease.

For other groups, a 1958 paper by Schwartz and Casley-Smith indicated that the Australian aborigines also had atherosclerosis (8,9). That same year based on another study, the researchers questioned the role of blood cholesterol (10):

If hypercholesterolemia is the prime causal mechanism of human atherosclerosis, one might expect that the lipid abnormality would be universally present in every individual examined. This is not so, and we are therefore forced to question the role of hypercholesterolemia in human atherosclerosis.

They also made the important point that "to infer a causal relationship on the basis of a statistical correlation between two variables is very dangerous" (10).

Because of this critical mindset, Schwartz and Casley-Smith avoided the error of attributing the lower incidence of atherosclerosis in Australian aborigines to lower cholesterol levels (10):

It is concluded that the serum cholesterol level of the Australian aborigines is lower than that of the white controls because of the lower intake of animal fat. However, this low level of cholesterol is not suggested as the reason for the lower incidence of atherosclerosis in this ethnic group.

More recently in 2017, Kaplan et al. found a low prevalence of coronary calcium in the South American Tsimane (11), but we have no data on other aspects of the disease (excess intimal thickening, fatty streaks, etc.) that are likely more prevalent.

Similar to industrialized populations, LDL was not a predictor of coronary calcium in the Tsimane:

Significant predictors of a CAC [coronary artery calcium] score greater than 0 were age, body-fat percentage, hs-CRP, and erythrocyte sedimentation rate.

Nor did LDL have an association with thoracic aortic calcium (12):

Inflammatory markers and LDL were not associated with TAC [thoracic aortic calcium] presence or amount.

The Bottom Line

Given the evidence, I have no choice but to agree with Bjørklund and colleagues (13):

To claim that atherosclerosis is solely a disease of modern man is not supported by palaeopathological studies. . . . It is generally the case, if sought, that atherosclerosis is found in most species, e.g., carnivore, pinnipedia, elephants, mammoths, primates, rabbits, etc., although with some mammalian species being much more vulnerable than others, so it is not surprising at all that atherosclerosis is present in mummies.

Thus, although atherosclerosis may be less severe in hunter-gatherers, they nevertheless do have atherosclerosis. And this appears to be the case regardless of their LDL levels.

Atherosclerosis and Angiography

Next, O’Keefe and colleagues claim:

Abundant data from prospective trials reveal a strong and direct relationship between on-treatment LDL level and rate of atherosclerotic progression. These randomized controlled trials show that whether patients were on statin therapy or placebo, the rate of angiographic progression of atherosclerosis was closely related to the chronic LDL level.

Here, they cite seven statin trials: REGRESS, MARS, MAAS, CCAIT, PLAC-I, LCAS, and REVERSAL.

Besides ignoring methodological problems with these trials, O’Keefe and colleagues ignore the fact that statins have LDL-independent effects (anti-inflammatory, anti-thrombotic, etc.) — often called "pleiotropic" effects.

Thus, as one lipid scientist notes, an alleged benefit of statins "does not prove that cholesterol (many steps downstream from mevalonate) is a causal agent in CVD [cardiovascular disease]" (14).

What's more, if we analyze these seven trials, it becomes apparent that there is actually little to no association between angiographic progression of atherosclerosis and LDL cholesterol.

The Seven Trials: Within-Study Analyses

First, REGRESS found "no clear relation" between lipid values and the fraction of progressing or regressing patients (15). And two years later, a substudy of REGRESS reported that Lp(a) and HDL predicted disease, not LDL cholesterol (16):

In-trial apolipoprotein(a) and in-trial HDL cholesterol, but not in-trial LDL cholesterol, predicted the course of CAD [coronary artery disease] in normal to moderately hypercholesterolemic men.

Second, MARS did not find evidence of a relation between LDL cholesterol and lesion progression (17). The investigators rightly noted that several studies failed to show a relation (18):

Although LDL cholesterol is an established risk factor for CAD, it has failed to show a relation to coronary artery lesion progression in several studies. This has been particularly evident in studies that have been reported with separation of IDL from LDL. As in this study, IDL but not total LDL was associated with CAD progression.

Third, the MAAS investigators stated (19):

There was no significant correlation between the extent of LDL change and the extent of change in minimum lumen diameter.

Fourth, CCAIT showed no clear relations between LDL and angiographic changes (20). On the other hand, HDL had more consistent relations:

In lovastatin-treated patients, coronary change score did not correlate with plasma LDL cholesterol levels before or during treatment or with the percent change in LDL cholesterol. Coronary change score did correlate with HDL cholesterol levels before and during treatment.

Fifth, analysis of PLAC-I showed an association for small LDL particles but not the larger cholesterol-rich LDL particles, suggesting that LDL cholesterol had nothing to do with the angiographic changes (21):

Baseline levels of LDL cholesterol in the present study were associated with disease progression in the placebo group. This association, however, was attributable to the small LDL subclass; progression was not associated with levels of the larger LDL subclasses.

Sixth, despite similar on-treatment LDL levels, subjects with low HDL levels in LCAS appeared to get the greatest angiographic benefit (22). But changes in LDL and HDL were not associated with benefit (23):

The baseline characteristics of patients in the LCAS indicate that insulin resistance may increase risk for CAD independent of LDL cholesterol. Treatment with fluvastatin decreased progression of CAD and reduced the occurrence of clinical events among this high-risk group with insulin resistance. These benefits were not associated with the magnitude of changes in LDL or HDL cholesterol during treatment.

And seventh, researchers of REVERSAL admitted that LDL had "relatively weak correlations" with disease (possibly none if analyzed within each statin group) (24). In a later paper, they found no evidence of a relation for LDL, neither by angiographic nor IVUS measures (25):

Low-density lipoprotein and C-reactive protein were not significant predictors of greater disease burden. . . . The apparent lack of association between lipids and atheroma burden is consistent with other available data.

More Data

Also interesting are the studies O’Keefe and colleagues did not cite.

Take the conclusion from the Montreal Heart Study in 1993, which evaluated lipids and lipoproteins in relation to coronary angiographic changes (26):

High-density lipoprotein cholesterol was inversely related to the mean percentage increase in coronary artery stenosis in both men and women. Neither plasma triglycerides nor low-density lipoprotein cholesterol, triglycerides, or apolipoprotein B was related to change in stenosis . . .

This is no anomaly. A year later in 1994, investigators of the HARP trial stated (27):

No significant correlation was found between lesion changes and plasma lipid concentrations at baseline or changes in plasma lipid concentrations during the trial.

Likewise, here is the conclusion from Romm et al. in 1991 (28):

Neither total nor LDL cholesterol levels were related to any of the end points we examined . . . HDL cholesterol was the only independent variable associated with severity in these patients, whereas extent was associated with age and male gender and was unrelated to any of the lipid variables. Thus, a low total cholesterol level, per se, does not necessarily signify a low risk of developing CAD.

Or, we could cite SCIMO, where fish oil produced beneficial angiographic changes despite slight increases in LDL cholesterol (29):

Coronary segments in the fish oil group showed less progression and more regression than did coronary segments in the placebo group . . . Interestingly, low density lipoprotein (LDL)- cholesterol levels tended to be higher in the fish oil group, at certain time points significantly so . . .

The point is: According to O’Keefe and colleagues' own cited data and other data they failed to cite, LDL cholesterol has little to no association with angiographic progression of atherosclerosis.

Flawed Models

So far, the data provided are based on within-study analyses. But at this point, the reader might be wondering: If there is little to no association between LDL and disease, how could anyone claim a "strong and direct relationship" between the two?

Well, rather than admit a poor relationship between LDL and disease, O’Keefe and colleagues decided to conjure up an across-trial or study-level correlation. This is seen in the following image:

(Image: Although this graph contains "randomized" trials, it is actually an ecological correlation very prone to biases, including confounding and aggregation bias)

A similar graph could be made for HDL cholesterol — a marker many LDL-lowering supporters claim is non-causal:

(Image: Taken from reference 30)

These types of analyses may be common in the literature today, but they suffer from many pitfalls that render their results "deceptive and untrustworthy" (31).

As Cragg and colleagues noted, we should first establish an individual-level correlation to avoid aggregation bias or the ecological fallacy (32):

Researchers must first look at individual correlations to link outcomes (to avoid the ecological fallacy), and then work further to clearly establish causality.

But O’Keefe and colleagues haven't even established a credible association, let alone causation.

False and Irrelevant Predictions

From their flawed model, O’Keefe and colleagues claim that atherosclerosis does not progress when LDL is 67 mg/dl or below:

This regression line indicates that atherosclerosis does not progress when LDL is 67 mg/dl or below.

This prediction, however, was already undermined the year before their paper. In 2003, Hecht and Harman conducted a study showing that a mean LDL cholesterol of 65 mg/dL was still associated with plaque progression.

To quote (33):

This study demonstrates that, with respect to LDL cholesterol lowering, “lower is better” is not supported by changes in calcified plaque progression after 1.2 years of therapy . . . Further lowering to a mean of 65 mg/dl in the ≤ 80 mg/dl cohort did not slow the rate of calcified plaque progression . . .

And later data would confirm these findings.

In 2017, Spence and Solo observed a large percentage of individuals with plaque progression despite having LDL levels less than 70 mg/dL and even less than 38 mg/dL. The change in LDL also showed no association with plaque progression or regression.

As stated (34):

Many patients with LDL-C <1.8 mmol/L [<70 mg/dL] had plaque progression (47.5%), and change in LDL-C was not correlated with plaque progression/regression.

We see a similar disassociation between LDL and atherosclerosis in subjects who do not use LDL-lowering drugs.

In 2021, Inoue et al. divided 666 patients into three groups based on their LDL level: < 70 mg/dL, 70 to 99 mg/dL, and ≥ 100 mg/dL. They concluded that the low LDL group, with a mean LDL level of 57 mg/dL, did not have less atherosclerosis than the higher LDL groups (35):

We showed that LDL-C < 70 mg/ dL or < 100 mg/dL under no anti-lipidemic therapies was not associated with the presence or severity of CAD. These results indicated that we need to screen with CCTA to prevent primary events regardless of LDL-C levels.

O’Keefe and colleagues, in fact, cited two further trials (ARBITER and ASAP) inconsistent with their claims. Both these trials apparently showed regression of atherosclerosis (i.e., shrinkage of plaque) with statin treatment. But average on-treatment LDL levels were 76 mg/dL and 150 mg/dL, respectively (36,37).

Thus, in one paragraph, O’Keefe and colleagues are claiming that atherosclerosis does not progress when LDL is 67 mg/dl or below. Yet, in another paragraph, they are citing trials with not only non-progression but also regression of atherosclerosis at LDL levels above 67 mg/dL.

Likewise, many other reports claimed regression of atherosclerosis in a substantial number of patients with LDL levels above 100 mg/dL and with average LDL levels as high as 172 mg/dL (34,38-40).

Even the popular ASTEROID study concluded that a high percentage of subjects had atheroma regression "regardless of the LDL cholesterol achieved" (41):

(Image: Regardless of LDL levels achieved, a similar percentage of subjects demonstrated atheroma regression, including those with LDL levels of 100 mg/dL or greater)

Thus, the data would suggest that, on an individual level, progression and regression of atherosclerosis occur across a wide range of LDL levels, and that LDL levels explain little to nothing of the variation in disease.

(Image: Taken from reference 42. Atherosclerosis progression and regression can apparently occur at any level of LDL cholesterol, consistent with its non-causal role)

In short, the strong correlation between LDL and disease that O’Keefe and colleagues claim from study-level data (r = 0.78) is not supported by within-study or individual-level analyses. Not even close.

Unintended Benefits On Inflammation?

In the last paragraph of their paper, O’Keefe and colleagues suggest that lowering LDL would have "unintended benefits," like lower inflammation:

Inflammation and endothelial dysfunction, both important markers of abnormal vascular biology, have been shown to be improved as LDL is lowered to <80 mg/dl

The two studies they cited in support of this statement (PROVE-IT and REVERSAL) did not have analyses for endothelial function, but analyses between LDL and a biomarker of inflammation (CRP) only turned up weak to non-existent correlations.

Here is the individual-level correlation between LDL and CRP from PROVE-IT (43):

(Image: In PROVE-IT, the correlation was so weak that less than 3% of the variation in achieved CRP levels was "explained" by the variation in achieved LDL cholesterol levels)

In REVERSAL, the correlation was even weaker, and no evidence of a correlation was found in each statin group alone (24). This lack of correlation between LDL and CRP is consistent with other trials — all available to O’Keefe and colleagues at the time (44-47).

In 2012, in fact, Bots et al. nicely illustrated the perils of study-level correlations using LDL and CRP. They noted that based on study-level data (averages), there seemed to be a strong relation between LDL lowering and CRP lowering. Yet, in a trial of almost 1000 participants, they found no individual-level relation between LDL and CRP (48):

This is not to say that study-level and individual-level data are always at odds. For example, a 2022 study-level analysis did not find a relationship between LDL and CRP (49):

Linear association between changes in LDL-C level and CRP concentration was not demonstrated in this study. This result suggested that the anti-inflammation effect of statins and ezetimibe is independent of their effect on the reduction of LDL-C level.

We also know that under certain conditions, lower lipid levels are associated with higher CRP levels (50-53).

In any case, conventional wisdom admits that LDL itself "has no significant atherogenic properties" (54). Therefore, an inflammatory response is usually attributed to modified forms of LDL (55):

Native LDL does not present any of the typical features of an atherogenic lipoprotein. It is not inflammatory, apoptotic or recognized by scavenger receptors. Furthermore, its binding to arterial proteoglycans is low. Therefore, there is a general consensus that LDL must be modified in order to acquire atherogenic characteristics.

As noted in Part 1, O’Keefe and colleagues stated:

In an atherogenic millieu, oxidized LDL infiltrates the intima where it stimulates inflammation, endothelial dysfunction, and eventually atherosclerosis.

But if it is oxidized LDL that stimulates inflammation and other aspects related to atherosclerosis, then they should emphasize this rather than giving the impression throughout the paper that LDL per se is responsible.

Conclusions

On the topic of atherosclerosis, O’Keefe and colleagues' paper has many flaws, including:

  • False claims about hunter-gatherers.

  • Failure to acknowledge the large amounts of contradicting data.

  • No consideration of the methodological limitations of the studies.

  • No mention of the fatal limitations of imaging methods like angiography (56).

  • Failure to acknowledge the questionable clinical relevance of small changes in atherosclerosis (57).

  • Failure to consider the pleiotropic effects of statins (58).

  • Failure to distinguish between the effects of modified LDL and native LDL.

  • No awareness that correlations based on aggregated data could mislead and often do not apply at the relevant individual level.


Go to Part 3.


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